The present invention relates to compounds that act to block calcium channels; methods of using the compounds to treat stroke, cerebral ischemia, pain, head trauma or epilepsy; and to pharmaceutical compositions that contain the compounds of the present invention.
The entry of excessive amounts of calcium ions into neurons following an ischemic episode or other neuronal trauma has been well-documented. Uncontrolled high concentrations of calcium in neurons initiates a cascade of biochemical events that disrupts normal cellular processes. Among these events are the activation of proteases and lipases, breakdown of neuronal membranes and the formation of free radicals, which may ultimately lead to cell death. Several types of calcium channels have been discovered and called the L, N, P, Q, R, and T types. Each type possesses distinct structural features, functional properties and cellular/subcellular distributions. Type selective calcium channel blockers have been identified. For example, SNX-111 has been shown to be a selective N-type calcium channel blocker and has demonstrated activity in a number of models of ischemia and pain (Bowersox S. S., et al., Drug News and Perspective, 1994;7:261-268 and references cited therein). The compounds of the present invention are calcium channel blockers that can block N-type calcium channels and can be used to treat stroke, pain, cerebral ischemia, head trauma, and epilepsy.
Certain benzhydryl amides and benzhydryl amines have been described in the past, but their methods of use have been different from those of the present invention. For instance, U.S. Pat. No. 4,596,803 disclosed the following compound for the treatment of cardiac problems, with no mode of action specified: 
European Patent Publication 333,938 refers to compounds having beta blocking activity for use in treatment of cardiovascular disorders. World Patent Publication 96/05201 refers to imidazopyridine derivatives as dual histamine and platelet activating factor antagonists. U.S. Pat. No. 4,764,514 refers to an oxothiazolidine compound. Other benzhydryl amides are mentioned in Acta. Polon. Pharm. 34(4):371-375; 34(5):459-463; and 39(3):261-266. None of these earlier compounds have been used as N-type calcium channel blockers as described in the present invention.
The compounds of the present invention are not homologs or positional isomers of the compounds specified by Masaki et al.; therefore, one skilled in the art could not predict if these compounds would have similar biological activities.
The present invention provides compounds having the structural Formula I 
or the pharmaceutically acceptable salts, thereof, wherein:
X is xe2x80x94NH(CH2)nxe2x80x94
each R1 and R2 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, 
R1 and R2 together with the nitrogen atom to which they are both attached form a heterocycloalkyl group;
R3 is hydrogen, C1-C6 alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, or xe2x80x94(CH2)nxe2x80x94C3-C7 cycloalkyl;
R4 is hydrogen or C1-C6 alkyl;
or R3 and R4 together with the carbon atom to which they are attached form a C3-C7 cycloalkyl ring;
each R5 and R6 are independently phenyl or substituted phenyl;
R7 is C1-C6 alkyl, phenyl, or heterocycloalkyl; and
each n is independent 0 to 6.
In another preferred embodiment,
R1 is hydrogen and 
In another preferred embodiment, R3 is hydrogen and
R4 is 2-methylpropyl.
In another preferred embodiment, R5 and R6 are 4-fluorophenyl.
In another preferred embodiment, X is xe2x80x94NHCH2CH2CH2xe2x80x94.
In another preferred embodiment, R5 and R6 are phenyl.
In another preferred embodiment, R5 and R6 are 4-fluorophenyl or phenyl;
X is xe2x80x94NHCH2CH2CH2xe2x80x94;
R3 is hydrogen; and
R4 is 2-methylpropyl.
In a preferred embodiment of the compounds of Formula I,
X is 
R1 is hydrogen;
R2 is 
xe2x80x83and
R5 and R6 are 4-fluorophenyl or phenyl.
The present invention provides the compound (S)-Azepane-1-carboxylic acid {3-methyl-1-[3-(1-methyl-2-oxo-3-phenyl-2,3-dihydro-1H-indol-3-yl)-propylcarbamoyl]-butyl}-amide.
The present invention provides the compound (S)-Azepane-1-carboxylic acid {3-methyl-1-[(1-phenyl-1H-indazol-3-ylmethyl)-carbamoyl]-butyl}-amide.
The present invention provides the compound (S)-Azepane-1-carboxylic acid {1-[4-(9H-fluoren-9-yl)-piperazine-1-carbonyl]-3-methyl-butyl}-amide.
The present invention provides the compound (S)-(1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-ylmethyl}-3-methyl-butyl)-carbamic acid tert-butyl ester.
The present invention provides the compound (S)-Azepane-1-carboxylic acid (1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-ylmethyl}-3-methyl-butyl)-amide.
The present invention provides the compound (S)-Azepane-1-carboxylic acid [1-(benzhydryl-carbamoyl)-3-methyl-butyl]-amide.
The present invention provides the compound (S)-Azepane-1-carboxylic acid [1-(2,2-diphenyl-ethylcarbamoyl)-3-methyl-butyl]-amide.
The present invention also provides the compounds:
(S)-Azepane-1-carboxylic acid {1-[4,4-bis-(4-fluoro-phenyl)-butylcarbamoyl]-3-methyl-butyl}-amide;
(R)-Azepane-1-carboxylic acid {1-[4,4-bis-(4-fluoro-phenyl)-butylcarbamoyl]-3-methyl-butyl}-amide;
(S)-Azepane-1-carboxylic acid [1-(3,3-diphenyl-propylcarbamoyl)-3-methyl-butyl]-amide;
(S)-{1-[4,4-Bis-(4-fluoro-phenyl)-butylcarbamoyl]-3-methyl-butyl}-carbamic acid tert-butyl ester;
(S)-2-Amino-4-methyl-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-2-(Cyclohexylmethyl-amino)-4-methyl-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-4-Methyl-2-(3-methyl-but-2-enylamino)-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-4-Methyl-2-methylamino-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-4-Methyl-2-[methyl-(3-methyl-but-2-enyl)-amino]-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-2-Cyclohexylamino-4-methyl-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-Azepane-1-carboxylic acid {1-[4,4-bis-(4-fluoro-phenyl)-butylcarbamoyl]-2-methyl-butyl}-amide;
(S)-4-Phenyl-piperazine-1-carboxylic acid {1-[4,4-bis-(4-fluoro-phenyl)-butylcarbamoyl]-3-methyl-butyl}-amide;
(S)-4-Methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-2-Isopropylamino-4-methyl-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-2-Dimethylamino-4-methyl-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-4-Methyl-2-piperidin-1-yl-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-4-Methyl-2-morpholin-4-yl-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-4-Methyl-2-piperidin-1-yl-pentanoic acid (3,3-diphenyl-propyl)-amide;
(S)-2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid (3,3-diphenyl-propyl)-amide;
(S)-Azepane-1-carboxylic acid {1-[4,4-bis-(4-fluoro-phenyl)-butylcarbamoyl]-2-methyl-propyl}-amide;
(S)-4-Methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-4-Methyl-piperazine-1-carboxylic acid {1-[4,4-bis-(4-fluoro-phenyl)-butylcarbamoyl]-3-methyl-butyl}-amide;
(S)-Azepane-1-carboxylic acid {1-[4,4-bis-(4-fluoro-phenyl)-butylcarbamoyl]-ethyl}-amide;
(S)-Azepane-1-carboxylic acid (1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazine-1-carbonyl}-3-methyl-butyl)-amide;
(S)-Azepane-1-carboxylic acid (2-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-2-oxo-ethyl)-amide;
(S)-Azepane-1-carboxylic acid (1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazine-1-carbonyl)-2-methyl-propyl)-amide;
(R)-Azepane-1-carboxylic acid (1-{4-[bis-(4-fluoro-phenyl)-methyl]-1-piperazine-1-carbonyl}-3-methyl-butyl)-amide;
(S)-1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}4-methyl-2-piperidin-1-yl-pentan-1-one;
(S)-1-{4-[Bis-(4-fluoro-phenyl)methyl]-piperazin-1-yl}-2-cyclohexylamino-4-methyl-pentan-1-one;
(S)-1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-2-dimethylamino-4-methyl-pentan-1-one;
(S)-1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-2-(cyclohexyl-methyl-amino)-4-methyl-pentan-1-one;
(S)-1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-4-methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentan-1-one;
(S)-1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-4-methyl-2-morpholin-4-yl-pentan-1-one;
(S)-Azepane-1-carboxylic acid (1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazine-1-carbonyl}-2-methyl-butyl)-amide;
(S)-4-Phenyl-piperazine-1-carboxylic acid (1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazine-1-carbonyl}-3-methyl-butyl)-amide;
1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-4-methyl-2-[methyl-(3-methyl-butyl)-amino]-pentan-1-one;
(S)-4-Methyl-piperazine-1-carboxylic acid (1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazine-1-carbonyl}-3-methyl-butyl)-amide;
(S)-Azepane-1-carboxylic acid [1-(4-benzhydryl-piperazine-1-carbonyl)-3-methyl-butyl]-amide;
(S)-1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-2-isopropylamino-4-methyl-pentan-1-one;
(S)-(1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazine-1-carbonyl}-3-methyl-butyl)-carbamic acid tert-butyl ester;
(S)-(1-Benzyl-2-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-2-oxo-ethyl)-carbamic acid tert-butyl ester;
(S)-2-Amino-1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-3-phenyl -propan-1-one;
(S)-2-Amino-1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-4-methyl-pentan-1-one;
(S)-1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-2-isopropylamino-3-phenyl-propan-1-one;
(S)-1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-2-(3-methyl-butylamino)-3-phenyl-propan-1-one;
(S)-1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-2-[bis-(3-methyl-butyl)-amino]-3-phenyl-propan-1-one;
(S)-2-[Bis-(4-tert-butoxy-benzyl)-amino]-1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}4-methyl-pentan-1-one;
1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-2-(4-tert-butyl-benzylamino)-4-methyl-pentan-1-one;
(S)-2-[Bis-(4-tert-butyl-benzyl)-amino]-1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-4-methyl-pentan-1-one;
1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-4-methyl-2-(3,4,5-trimethoxy-benzylamino)-pentan-1-one;
1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-2-cyclohexylamino-3-phenyl-propan-1-one;
S-2-Benzylamino-1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-4-methyl-pentan-1-one;
S-1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-4-methyl-2-(tetrahydro-pyran-4-ylamino)-pentan-1-one;
S-1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-2-(4-tert-butoxy-benzylamino)-4-methyl-pentan-1-one;
S-N-[4,4-Bis-(4-fluoro-phenyl)-butyl]-2-isopropylamino-3-methyl)-butyramide;
S-N-[4,4-Bis-(4-fluoro-phenyl)-butyl]-2-sec-butylamino-3-methyl-butyramide;
S-{4-[4,4-Bis-(4-fluoro-phenyl)-butylcarbamoyl]-4-tert-butoxycarbonylamino-butyl}-carbamic acid tert-butyl ester;
S-2-(Isopropyl-methyl-amino)-4-methyl-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
S-N-[4,4-Bis-(4-fluoro-phenyl)-butyl]-2-(cyclohexyl-methyl-amino)-3-methyl-butyramide;
S-N-[4,4-Bis-(4-fluoro-phenyl)-butyl]-2-cyclohexylamino-3-methyl-butyramide;
(R)-4-methyl-2-methylamino-pentanoic acid [4,4-bis-(4-fluorophenyl)-butyl]-amide;
(S)-2-Hydroxy-4-methyl-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-3-Methyl-2-methylamino-butanoic acid [4,4-bis-(4-fluorophenyl)-butyl]-amide;
N-[4,4-Bis-(4-fluoro-phenyl)-butyl]-2-methylamino-acetamide;
(S)-4-Ethyl-2-methylamino-pentanoic acid [4,4-bis-(4-fluorophenyl)butyl]-amide;
(S)-N1-[4,4-Bis-(4-fluoro-phenyl)-butyl]-4-N2-dimethyl-pentane-1,2-diamine;
(R)-N1-[4,4-Bis-(4-fluoro-phenyl)-butyl]-4-N2-dimethyl-pentane-1,2-diamine;
N-[4,4-Bis-(4-fluoro-phenyl)-butyl]-2-(isobutyl-methyl-amino)-acetamide;
(R)-N-[4,4-Bis-(4-fluoro-phenyl)-butyl]-2-methylamino-propionamide;
(S){1-[4,4-Bis-(4-fluoro-phenyl)-butylcarbamoyl]-2-methyl-propyl)-methyl-carbamic acid tert-butyl ester;
(S)N-[4,4-Bis-(4-fluoro-phenyl)-butyl]-3-methyl-2-methylamino-butyramide;
(S){1-[4,4-Bis-(4-fluoro-phenyl)-butylcarbamoyl]-2-methyl-butyl}-methyl-carbamic acid tert-butyl ester;
(S)3-Methyl-2-methylamino-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S){1-[4,4-Bis-(4-fluoro-phenyl)-butylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester;
(S)N-[4,4-Bis-(4-fluoro-phenyl)-butyl]-2-methylamino-propionamide;
(S){1-[4,4-Bis-(4-fluoro-phenyl)-butylcarbamoyl]-2-cyclohexyl-ethyl}-methyl-carbamic acid tert-butyl ester;
(S)N-[4,4-Bis-(4-fluoro-phenyl)-butyl]-3-cyclohexyl-2-methylamino-propionamide;
(S){1-[4,4-Bis-(4-fluoro-phenyl)-butylcarbamoyl]-2-cyclohexyl-ethyl}-carbamic acid tert-butyl ester;
(S)2-Amino-N-[4,4-bis-(4-fluoro-phenyl)-butyl]-3-cyclohexyl-propionamide;
{1-[4,4-Bis-(4-fluoro-phenyl)-butylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester;
1-Amino-cyclohexanecarboxylic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
{1-[4,4-Bis-(4-fluoro-phenyl)-butylcarbamoyl]-cyclohexyl}-methyl-carbamic acid tert-butyl ester;
1-Methylamino-cyclohexanecarboxylic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
{1-[4,4-Bis-(4-fluoro-phenyl)-butylcarbamoyl]-cyclopentyl}-carbamic acid benzyl ester; and
1-Amino-cyclopentanecarboxylic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide.
Also provided is a method of blocking calcium channels in a cell, the method comprising contacting the cell with the compound according to Formula I.
In a preferred embodiment, the calcium channels are N-type calcium channels.
Also provided is a method of treating or preventing an N-type calcium channel mediated affliction in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of a compound of Formula I.
In a preferred embodiment, the affliction is stroke.
In a preferred embodiment, the affliction is cerebral ischemia.
In a preferred embodiment, the affliction is head trauma.
In a preferred embodiment, wherein the affliction is epilepsy.
In a preferred embodiment, wherein the affliction is pain.
Also provided is a pharmaceutical composition comprising a compound of Formula I.
The following terms are employed herein as defined below, except as may be expressly modified.
The term xe2x80x9calkylxe2x80x9d means a straight or branched chain hydrocarbon. Representative examples of alkyl groups are methyl, ethyl, propyl, isopropyl, isobutyl, butyl, tert-butyl, sec-butyl, pentyl, and hexyl.
Preferred alkyls are C1-C6 alkyls.
The term xe2x80x9calkoxyxe2x80x9d means an alkyl group attached to an oxygen atom. Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy, and isobutoxy.
The terms xe2x80x9chaloxe2x80x9d and xe2x80x9chalogenxe2x80x9d include chlorine, fluorine, bromine, and iodine.
The term xe2x80x9calkenylxe2x80x9d means a branched or straight chain hydrocarbon having one or more carbon-carbon double bond.
The term xe2x80x9cheteroatomxe2x80x9d means oxygen, nitrogen, sulfur, or phosphorus.
The term xe2x80x9ccycloalkylxe2x80x9d means a cyclic hydrocarbon. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocycloalkylxe2x80x9d means a 3- to 7-membered cycloalkyl moiety wherein one or more of the ring carbons is substituted by a heteroatom. Examples of heterocycles include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl.
The term xe2x80x9carylxe2x80x9d means an aromatic hydrocarbon. Representative examples of aryl groups include phenyl and naphthyl.
The term xe2x80x9cheteroarylxe2x80x9d means an aryl group wherein one or more carbon atom of the aromatic hydrocarbon has been replaced with a heteroatom. Examples of heteroaryl radicals include, but are not limited to, pyridyl, imidazolyl, pyrrolyl, thienyl, furyl, pyranyl, pyrimidinyl, pyridazinyl, indolyl, quinolyl, naphthyridinyl, and isoxazolyl.
The term xe2x80x9csubstitutedxe2x80x9d means that the base organic radical has one or more substituents. For example, substituted cyclohexyl means a cyclohexyl radical that has one or more substituents. Substituents include, but are not limited to, halogen, C1-C8 alkyl, xe2x80x94CN, CF3, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHC1xe2x80x94C8 alkyl, xe2x80x94N(C1-C8 alkyl)2, xe2x80x94OC1-C8 alkyl, and xe2x80x94OH. Particularly preferred substituents include, but are not limited to, tert-butyl, methyl, chlorine, fluorine, bromine, xe2x80x94OCH3, xe2x80x94OCH2CH3, xe2x80x94OH, and xe2x80x94N(CH3)2.
The symbol xe2x80x9cxe2x80x94xe2x80x9d means a bond.
The term xe2x80x9cpatientxe2x80x9d means all animals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, and pigs.
The following abbreviations are used throughout the application:
The compounds of the invention may be readily prepared as set forth in the following reaction scheme:
I. Amino acid synthesis was carried out by stepwise condensation of an aldehyde or ketone with a naturally occurring amino acid, followed by reduction. This sequence was repeated in order to prepare N,N-dialkyl amino acids, as illustrated below. 
II. Coupling procedures
1. For N,N-dialkyl substituted amino acids 
2. When the acids are secondary amino acids 
3. For N-acyl amino acids 
Each of the above variables Ra, Rc, Rd, Re, Rf, Rx, Rq, and Rz are defined as is consistent with the compounds disclosed herein.
Those skilled in the art are easily able to identify patients having a stroke or at risk of having a stroke, cerebral ischemia, head trauma, or epilepsy. For example, patients who are at risk of having a stroke include, but is not limited to, patients having hypertension or undergoing major surgery.
A therapeutically effective amount is an amount of a compound of Formula I that when administered to a patient, ameliorates a symptom of the disease.
The compounds of the present invention can be administered to a patient either alone or a part of a pharmaceutical composition. The compositions can be administered to patients either orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments, or drops), or as a buccal or nasal spray.
Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well-known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.
Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
Also included in the invention are pharmaceutically acceptable salts, esters, amides, and prodrugs of the compounds of the invention. The term xe2x80x9cpharmaceutically acceptable salts, esters, amides, and prodrugsxe2x80x9d as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term xe2x80x9csaltsxe2x80x9d refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laureate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, lumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate and laurylsulphonate salts, and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary anmonium and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. (See, for example, S. M. Berge et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. Pharm. Sci., 1977;66:1-19 which is incorporated herein by reference.)
Examples of pharmaceutically acceptable, non-toxic esters of the compounds of this invention include C1-C6 alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C5-C7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C1-C4 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods.
Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary C1-C6 alkyl amines and secondary C1-C6 dialkyl amines wherein the alkyl groups are straight or branched chain. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1-C3 alkyl primary amines, and C1-C2 dialkyl secondary amines are preferred. Amides of the compounds of the invention may be prepared according to conventional methods.
The term xe2x80x9cprodrugxe2x80x9d refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, xe2x80x9cPro-drugs as Novel Delivery Systems,xe2x80x9d Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
The compounds of the present invention can exist in different stereoisomeric forms by virtue of the presence of asymmetric centers in the compounds. It is contemplated that all stereoisomeric forms of the compounds, as well as mixtures thereof including racemic mixtures, form part of this invention.
The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is preferable. The specific dosage used, however, can vary. For example, the dosage can depend on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well-known to those skilled in the art.
The compounds of the invention are also useful research tools for studying the biological, cellular effects of blocking N-type calcium channels.
In addition, it is intended that the present invention cover compounds made either using standard organic synthetic techniques, including combinatorial chemistry or by biological methods, such as through metabolism.